The 'ABC' of GABA receptors: A brief review

1, In the mammalian central nervous system, GABA is the main inhibitory neurotransmitter, GABA is a highly flexible molecule and, thus, can exist in many low-energy conformations. Conformationally restricted analogues of GABA have been used to help identify three major GABA receptors, termed GABAA, GABA(B) and GABA(C) receptors, 2. GABAA and GABA(C) receptors are members of a superfamily of transmitter-gated ion channels that include nicotinic acetylcholine, strychnine-sensitive glycine and 5HT(3) receptors, GABAA receptors are hetero-oligomeric Cl- channels that are selectively blocked by the alkaloid bicuculline and modulated by steroids, barbiturates and benzodiazepines. To date, 16 human GABAA receptor cDNA have been cloned. 3, GABA(B) receptors are seven transmembrane receptors that are coupled to G-proteins and activate second messenger systems and Ca2+ and K+ ion channels. To date, three GABA(B) receptor proteins have been cloned and these resemble metabotropic glutamate receptors, GADA(B) receptors are hetero-oligomeric receptors made up of a mixture of a combination of the subunits, These receptors are selectively activated by (-)-baclofen and CCGP27492 and are blocked by phaclofen, the phosphonic acid analogue of baclofen, 4. In contrast, GABA(C) receptors represent a relatively simple form of transmitter-gated Cl- channel made up of a single type of protein subunit, Two human GABA(C) receptor cDNA have been cloned. These receptors are not blocked by bicuculline nor are they modulated by steroids, barbiturates or benzodiazepines. Instead, GABA(C) receptors are selectively activated by the conformationally restricted analogues of GABA in the folded conformation cis-4-aminocrotonic acid and (1S,2R)-2-(aminomethyl)-1-carboxycyclopropane (1,2,5,6-Tetrahydropyridine-4-yl)methylphosphinic acid, a methylphosphinic acid analogue of GABA in a partially folded conformation, is a selective antagonist at GABA(C) receptors.